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However, their health is threatened by multiple interacting stressors, including pesticides, pathogens, and nutritional changes. We tested the hypothesis that distinct agricultural ecosystems\u2014with different combinations of agrochemical exposure, pathogen loads, and floral resources\u2014elicit ecosystem\u2010specific, tissue\u2010level molecular responses in honey bees. We conducted an integrated multi\u2010omics analysis using RNA\u2010sequencing (RNA\u2010seq), proteomics, and gut microbiome profiling across three key tissue types (head, abdomen, and gut) of honey bees collected from two agroecosystems over two field seasons. Quantification was performed for pesticide residues, pathogen loads (\n Nosema<\/jats:italic>\n spp.,\n Varroa destructor<\/jats:italic>\n , and multiple viruses), and gut microbiota. Weighted gene co\u2010expression network analysis (WGCNA) revealed tissue\u2010specific protein modules with ecosystem\u2010associated patterns, which differed from RNA co\u2010expression networks. Microbiome composition also varied, with key genera like\n Gilliamella, Snodgrassella, and Bartonella<\/jats:italic>\n correlating with metabolic modules. These findings underscore the complex, environment\u2010dependent impacts of agroecosystem conditions on bee health. Our study provides a system\u2010level understanding of how combined pesticide, pathogen, and parasitic stressors, mediated by diet and microbiome, shape molecular phenotypes in honey bees\u2014informing strategies for pollinator protection in managed landscapes.\n <\/jats:p>\n <\/jats:sec>\n \n Summary<\/jats:title>\n \n \n \n This study provides a comprehensive multi\u2010omics analysis of honey bees foraging in blueberry and cranberry agroecosystems, offering novel insights into the molecular mechanisms underlying pollinator health in managed crop environments.<\/jats:p>\n <\/jats:list-item>\n \n \n By integrating transcriptomic, proteomic, and microbiome profiling across key tissues\u2014head, abdomen, and gut\u2014we reveal how environmental stressors, including pesticide exposure, pathogen infections, and parasitic infestations (e.g.,\n Varroa destructor<\/jats:italic>\n ), differentially impact bee physiology and microbiome composition.\n <\/jats:p>\n <\/jats:list-item>\n \n Our findings highlight tissue\u2010specific responses to these stressors, with distinct metabolic pathway alterations observed in each tissue.<\/jats:p>\n <\/jats:list-item>\n \n Proteomic and transcriptomic analyses uncovered dysregulated pathways linked to oxidative phosphorylation and protein synthesis, while microbiome analysis revealed crop\u2010dependent shifts in gut bacterial communities, suggesting potential roles in pesticide detoxification and immune modulation.<\/jats:p>\n <\/jats:list-item>\n \n Notably, we identified key molecular biomarkers associated with stress adaptation, which may serve as early indicators of colony health deterioration.<\/jats:p>\n <\/jats:list-item>\n \n This research underscores the need for a system\u2010level approach to understanding pollinator stress in agricultural landscapes.<\/jats:p>\n <\/jats:list-item>\n \n By elucidating the interactions between diet, pesticide residues, pathogen loads, and molecular stress responses, our study provides a foundation for targeted conservation strategies aimed at mitigating environmental risks and improving pollination sustainability in agroecosystems.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/pmic.70033","type":"journal-article","created":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T07:54:56Z","timestamp":1757145296000},"page":"41-57","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Omics Insights Into the Effects of Highbush Blueberry and Cranberry Crop Agroecosystems on Honey Bee Health and Physiology"],"prefix":"10.1002","volume":"26","author":[{"given":"Huan","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Michael Smith Laboratories Life Sciences Institute University of British Columbia Vancouver British Columbia 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